Search

© 2016 The Author(s). Background: Although classified as metal oxides, cobalt monoxide (CoO) and lanthanum oxide (La2O3) nanoparticles, as representative transition and rare earth oxides, exhibit distinct material properties that may result in different hazardous potential in the lung. The current study was undertaken to compare the pulmonary effects of aerosolized whole body inhalation of these nanoparticles in mice. Results: Mice were exposed to filtered air (control) and 10 or 30 mg/m3of each particle type for 4 days and then examined at 1 h, 1, 7 and 56 days post-exposure. The whole lung burden 1 h after the 4 day inhalation of CoO nanoparticles was 25 % of that for La2O3nanoparticles. At 56 days post exposure, < 1 % of CoO nanoparticles remained in the lungs; however, 22-50 % of the La2O3nanoparticles lung burden 1 h post exposure was retained at 56 days post exposure for low and high exposures. Significant accumulation of La2O3nanoparticles in the tracheobronchial lymph nodes was noted at 56 days post exposure. When exposed to phagolysosomal simulated fluid, La nanoparticles formed urchin-shaped LaPO4structures, suggesting that retention of this rare earth oxide nanoparticle may be due to complexation of cellular phosphates within lysosomes. CoO nanoparticles caused greater lactate dehydrogenase release in the bronchoalveolar fluid (BALF) compared to La2O3nanoparticles at 1 day post exposure, while BAL cell differentials indicate that La2O3nanoparticles generated more inflammatory cell infiltration at all doses and exposure points. Histopathological analysis showed acute inflammatory changes at 1 day after inhalation of either CoO or La2O3nanoparticles. Only the 30 mg/m3La2O3nanoparticles exposure caused chronic inflammatory changes and minimal fibrosis at day 56 post exposure. This is in agreement with activation of the NRLP3 inflammasome after in vitro exposure of differentiated THP-1 macrophages to La2O3but not after CoO nanoparticles exposure. Conclusion: Taken together, the inhalation studies confirmed the trend of our previous sub-acute aspiration study, which reported that CoO nanoparticles induced more acute pulmonary toxicity, while La2O3nanoparticles caused chronic inflammatory changes and minimal fibrosis.

This working group report is the product of the joint efforts of the members of an expert working group organized and convened by the International Life Sciences Institute Risk Science Institute. All members of the working group contributed by drafting various sections of the report. The final report emerged from extensive discussions and revisions by the working group and represents the consensus of the group on current utility and applicability of short-term assays and testing methods in screening fibers for potential toxicity. The screening strategy proposed by the working group is intended to distinguish between fibers that are unlikely to present a hazard and those that may require further testing for regulatory evaluation. The ILSI Risk Science Institute expresses it sincere thanks to the members of this working group for their tireless efforts over many months and their collegial spirit in developing this report. Financial support for this project through a cooperative agreement between the ILSI Risk Science Institute and the U. S. Environmental Protection Agency Office of Pollution Prevention and Toxics is gratefully acknowledged. The International Life Sciences Institute ( ILSI) is a nonprofit, worldwide foundation established in 1978 to advance the understanding of scientific issues relating to nutrition, food safety, toxicology, risk assessment, and the environment for the well being of the general public. ILSI receives financial support from industry, government, and foundations. The Risk Science Institute (RSI) was established in 1985 as part of the ILSI Research Foundation (RF) to improve the scientific basis of risk assessment. ILSI RF/RSI works toward this goal through an international program of scientific working groups, conferences and workshops, publications, and seminars. ILSI RF/RSI sponsors and participates in a wide range of activities to develop and disseminate new scientific knowledge, encourage exchange of ideas, and build consensus among scientists from academia, industry, government, and public interest/public health groups. ILSI RF/RSI and its programs are supported by government grants, cooperative agreements, and contracts, as well as by contributions from the ILSI Research Foundation and ILSI branches. For further information on ILSI, RF, and RSI, see the ILSI web site: www.ilsi.org.

On 23-24 March 1998, the International Life Sciences Institute (ILSI) Risk Science Institute convened a workshop entitled "Relevance of the Rat Lung Response to Particle Overload for Human Risk Assessment." The workshop addressed the numerous study reports of lung tumors in rats resulting from chronic inhalation exposures to poorly soluble, nonfibrous particles of low acute toxicity and not directly genotoxic. These poorly soluble particles, indicated by the acronym PSPs (e.g., carbon black, coal dust, diesel soot, nonasbestiform talc, and titanium dioxide), elicit tumors in rats when deposition overwhelms the clearance mechanisms of the lung resulting in a condition referred to as "overload." These PSPs have been shown not to induce tumors in mice and hamsters, and the available data in humans are consistently negative. The objectives were twofold: (1) to provide guidance for risk assessment on the interpretation of neoplastic and nonneoplastic responses of the rat lung to PSPs; and (2) to identify important data gaps in our understanding of the lung responses of rats and other species to PSPs. Utilizing the five critical reviews of relevant literature that follow herein and the combined expertise and experience of the 30 workshop participants, a number of questions were addressed. The consensus views of the workshop participants are presented in this report. Because it is still not known with certainty whether high lung burdens of PSPs can lead to lung cancer in humans via mechanisms similar to those of the rat, in the absence of mechanistic data to the contrary it must be assumed that the rat model can identify potential carcinogenic hazards to humans. Since the apparent responsiveness of the rat model at overload is dependent on coexistent chronic active inflammation and cell proliferation, at lower lung doses where chronic active inflammation and cell proliferation are not present, no lung cancer hazard is anticipated.